Gene Therapy for Adrenoleukodystrophy
Overview Adrenoleukodystrophy (ALD) is a disease that allows for the accumulation of long chain fatty acids in the body. There is a malfunction in the peroxisomal fatty acid beta oxidation process. While there are many tissues in the body affected by the build-up, the most affected are the myelin (in the central nervous system), the adrenal cortex, and the Leydig cells (in the testicles). When the myelin is degraded, it causes the nerves to lose function. This disease is an x-linked disorder, so it is most common in males. With that being said, about 50% of heterozygous females show symptoms later in life. The childhood cerebral form of the disease, which presents itself in 66% of patients, is the more severe type of ALD. The children that develop this form develop normally up until a certain point, and then there is a rapid degeneration to a vegetative state. The life expentancy of a child with this disease is between 1 and 10 years. In regards to the other forms of ALD, they range in severity and phenotypes. This disease is caused by a mutation in the ABCD1 gene located on the X chromosome. The estimated occurrence rate is 1:16,800. Symptoms The symptoms present in males and females are different because of the fact that this is a X-linked disease. There are seven possible phenotypes in males and five different phenotypes in females. In males, the most common symptoms of the cerebral form, in childhood, are instability, hyperactivity and disruptive behavior. If left untreated, this form can lead to a vegetative state and even death. In male adults, the most common symptoms are muscle stiffness and sexual dysfunction. All patients with this disease are known to have adrenal insufficiency. As of present, it is not possible to determine which form of the disease a person will get, as multiple phenotypes have been known to be present in the same family. The symptoms in females are similar but generally less severe. Gene Therapy While not used extensively yet, the use of gene therapy has been tested in patients where an appropriate match can be found. The process involves modifying appropriate lentiviral vectors to express the wild type ABCD1, instead of the mutant version. Lentiviral vectors are vectors that can infect both dividing and non-dividing cells and create longer lasting gene expression than other retroviruses. The lentiviral vector used in this process is derived from disabled versions of HIV. This vector is then transplanted into the patients using a process similar to a bone marrow or stem cell transplant. This process has been done mainly in France so far. The reasoning behind using gene therapy was that there was no match found for a traditional transplant. In most of the cases thus far, there has been success with resolving the demyelination process and lessening/resolving the neurological symptoms. With that being said, there are still high levels of the plasma VLCFA in the patient, even after gene therapy treatment. One big risk of gene therapy use is that the insertion of these vectors could mess with the normal biological function of the cell and could lead to leukemia. This outcome has not occurred in ALD treatment trials, but has in the gene therapy treatment of other diseases. Other Treatments The other treatments that are used address the symptoms of the disease, rather than the cause of the disease. * Dietary Treatment (ristricting intake of long chain fatty acids to reduce build-up) * Chemotherapy * Stem Cell Transplant * Bone Marrow Transplant (not used as commonly, because of the risks and challenges of using anotehr individual's bone marrow) * Hormone Replacement Therapy (to treat the adrenal insufficiency) Resources Wikipedia: Adrenoleukodystrophy Drug, Discovery and Development: First ALD Patient Gets New Gene Therapy Science Daily: Gene Therapy Technique Slows Brian Disease ALD WordPress: (ALD) Adrenoleukodystrophy The University of Arizona: Adrenoleukodystrophy, X-linked